Amelioration of joint disease in a rat model of collagen-induced arthritisby M40403, a superoxide dismutase mimetic

Objective. To investigate the effects of M40403, a synthetic mimetic of sup eroxide dismutase (SOD), on collagen-induced arthritis (CIA) in rats. Methods. CIA was elicited in Lewis rats by intradermal injection of 100 mul of an emulsion of bovine type II collagen (CII) in Freund's incomplete adj uvant at the base of the tail. A second injection was given on day 21. Results. Immunization induced an erosive arthritis of the hind paws. Macros copic evidence of CIA first appeared as periarticular erythema and edema in the hind paws by days 24-26 after the first injection, with a 100% inciden ce by days 27. Severity progressed over a 35-day period. Radiography reveal ed soft tissue swelling and focal resorption of bone, together with osteoph yte formation in the tibiotarsal joint. Histopathologic features included e rosion of the articular cartilage at the joint margins and subehondral bone resorption associated with bone-derived multinucleated cell-containing gra nulomatous lesions. Treatment with M40403 (2-10 mg/kg/day) starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26-35 an d improved the histologic findings in the joint and paw. Immunohistochemica l analysis for nitrotyrosine (a marker of peroxynitrite formation) and poly (ADP-ribose) polymerase (PARP; a nuclear enzyme activated by DNA single-str and damage) revealed positive staining in the inflamed joints of CII-treate d rats, suggestive of the formation of peroxynitrite and DNA damage, both o f which were markedly reduced by M40403 treatment. Radiographic evidence of protection from bone resorption, osteophyte formation, and soft tissue swe lling was apparent in the tibiotarsal joints of M40403-treated rats. Arthri tic rats treated with M40403 gained weight at the same rate and to the same extent as normal, nonarthritic rats. Conclusion. This study shows that a low molecular weight mimetic of SOD, M4 0403, attenuates the degree of chronic inflammation, tissue damage, and bon e damage associated with CIA in the rat, and supports the possible use of S OD mimetics as therapeutic agents for the management of chronic diseases su ch as rheumatoid arthritis.